TOLLIP optimizes dendritic cell maturation to LPS and Mycobacterium tuberculosis

TOLLIP is a central regulator of multiple innate immune signaling pathways, including TLR2, TLR4, IL-1R, and STING. Human TOLLIP deficiency, regulated by SNP rs5743854, is associated with increased tuberculosis (TB) risk and diminished frequency of BCG vaccine-specific CD4+ T cells in infants. How TOLLIP influences adaptive immune responses remains poorly understood. To understand the mechanistic relationship between TOLLIP and adaptive immune responses, we used human genetic and murine models to evaluate the role of TOLLIP in dendritic cell (DC) function. In healthy volunteers, TOLLIP SNP rs5743854 G allele was associated with decreased TOLLIP mRNA and protein expression in DCs, along with LPS-induced IL-12 secretion in peripheral blood DC. As in human cells, LPS-stimulated, Tollip −/− bone marrow-derived murine DCs secreted less IL-12 and expressed less CD40. Tollip was required in lung and lymph node-resident DCs for optimal induction of MHC Class II and CD40 expression during the first 28 days of Mtb infection in mixed bone marrow chimeric mice. Tollip −/− mice developed fewer Mtb-specific CD4+ T cells 28 days after infection, nor after BCG vaccination. Furthermore, Tollip −/− DC were unable to optimally induce T cell proliferation. Together, these data support a model where TOLLIP-deficient DCs undergo suboptimal maturation after Mtb infection, impairing T cell activation, and contributing to TB susceptibility.